Metabolism of hibernation
Hibernation is a highly effective overwintering strategy for the specialized animals that use it, and some of its underlying metabolic traits may benefit human health too. Here is what we in the Regan Lab are doing to better understand natural hibernation and its potential applications.
Hibernation is an adaptation to food scarcity during winter. It is the net manifestation of multiple underlying traits, and the most important of these is torpor. Torpor is a profound regulated depression of metabolism that reduces wintertime metabolic rate – and thus energy use – by up to 98% relative to typical summertime rates, when the animal is active. This allows hibernating animals to forego eating for multiple months each year and rely entirely on their fat reserves, effectively solving the problem of winter food scarcity.
We have learned a lot about hibernation over the past 100 or so years, but surprisingly, there is still a lot of fundamental stuff we do not understand. For example, we do not yet know how hibernators induce torpor, how they arouse from torpor, or how they avoid some of the potentially damaging effects of long-term torpor use. These knowledge gaps, coupled with hibernation’s ecological consequences and applied potential, make hibernation biology a dynamic research field.
Our hibernation research – basic
The overarching question we are currently investigating is, How is hibernation metabolism influenced by the hibernator’s seasonally shifting gut microbiota?
The gut microbiota is the community of microbes living in an animal’s gut. These microbes can affect a wide range of host metabolic processes via the metabolites they produce that are subsequently absorbed by the host. This is especially interesting with respect to hibernation because, at its core, hibernation is a metabolic strategy, the most striking example of metabolic plasticity among endothermic vertebrates. It is therefore reasonable to hypothesize that gut microbes contribute to hibernation metabolism, especially since the microbiota is known to shift seasonally in abundance, diversity and composition, altering the metabolic services it provides the host concurrent with the seasonal shifts in host metabolism. But researchers have only recently began investigating the crosstalk between hibernators and their gut microbes, and our understanding of these microbial contributions to hibernation metabolism is still in its infancy.
Together with a multidisciplinary group of researchers from the University of Wisconsin-Madison, we are using various stable isotope techniques to track the movement of metabolites between gut microbes and their model hibernator host, the 13-lined ground squirrel. We have recently discovered that, during hibernation, the squirrels harness a metabolic trick of their microbes to salvage nitrogen from waste urea, and then use that nitrogen – an essential ingredient in proteins – to synthesize new protein in the muscle and liver. This process is called urea nitrogen salvage (UNS), and it helps preserve the function of these important tissues during winter when the animals are fasting, inactive, and lack a dietary source of nitrogen. Gut microbes may therefore be major contributors to hibernators’ well-known ability to avoid muscle wasting during prolonged torpor use, an idea that has profound application potential (see applied research section below).
As well as continuing our urea nitrogen salvage research, we are also investigating the microbiota’s capacity to degrade other compounds such as carbohydrates (which decrease in the gut during hibernation) and host-derived mucin proteins (which remain present during hibernation), and evaluating how the molecular products of this degradation influence host metabolism.
Our hibernation research – applied
The overall applied biology question we are addressing is, Which particular muscle proteins benefit from urea nitrogen salvage (UNS)?
The microgravity environment of space invariably leads to a profound loss of muscle mass and performance, a phenomenon called spaceflight-induced disuse atrophy, is among the greatest challenges of long duration human spaceflight. Hibernating mammals, however, are remarkably resistant to muscle atrophy thanks in part to microbial-dependent UNS, which facilitates muscle protein synthesis throughout the inactive hibernation season. Humans too are capable of UNS, and though our abilities are modest compared with those of hibernators, this suggests that the necessary machinery for UNS is in place and potentially optimizable. Hibernating mammals may provide a blueprint for that optimization.
Our current work is taking the first step towards this by using isotopic-specific proteomics techniques to learn which particular muscle proteins UNS helps synthesize. We are comparing these proteins with those that are suppressed during spaceflight to learn whether this hibernation-related mechanism has the potential to serve as a microgravity countermeasure. The ultimate goal is to create a hibernation-like probiotic to facilitate atrophy resistance in astronauts. This could also potentially benefit humans on earth who experience muscle wasting for a variety of reasons, including bedrest, sarcopenia and malnourishment.
Regan MD, Chiang E, Liu Y, Tonelli M, Verdoorn KM, Gugel SR, Suen G, Carey HV, Assadi-Porter FM. 2022. Urea nitrogen recycling via gut symbionts increases in hibernating ground squirrels over the winter fast. Science 375 (6579), 460-463.
Regan MD, Chiang E, Martin SL, Porter WP, Assadi-Porter FM, Carey HV. 2019. Shifts in metabolic fuel use coincide with maximal rates of ventilation and body surface rewarming in arousing hibernators. American Journal of Physiology 316, R764-R775.
Top image: Thermal image of 13-lined ground squirrel arousing from torpor. Yellow indicates area of high metabolic activity. Photo by Matthew Regan.
Bottom image: 13-lined ground squirrels as drawn by John James Audubon, 1845.